3. The FDA’s Postmarketing Adverse Drug Experience Inspectional Program
Surveillance Programs Team
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration 1

4. AGENDA Postmarketing adverse drug experience reporting regulations
Role of headquarters and field
Inspectional strategies 2

5. Purpose of ADE Regulations
To obtain additional information on adverse events that may not have been detected prior to marketing
To improve the labeling of drug products 3

6. Brief Overview of Reporting Regulations
21 CFR Sections:
RX drugs not subject to approved applications
RX drugs subject to NDAs/ANDAs and OTCs associated with approved applications
RX drugs subject to AADAs 4

7. What is an Adverse Drug Experience?
Any adverse event associated with the use of drug in humans whether or not it is considered drug related. 5

8. Serious Adverse Drug Experience
Death
Life threatening (per initial reporter)
Permanently or significantly disabling
Hospitalization
Congenital anomaly/birth defect
Important medical events 6

9. Unexpected Adverse Drug Experience
Not listed in current labeling
Listed in labeling but greater specificity or severity
e.g. renal impairment listed, patient experiences renal failure 7

10. Reporting Requirements
Within 15 calendar days if Serious and Unexpected (domestic and foreign)
Follow-up information
Non-applicant notifies applicant within five calendar days 8

11. Periodic Report Quarterly and Annual Reports Serious & Expected ADEs
All Non-serious 9

12. When does the Regulatory Clock Start?
First day a firm or any affiliate receives event data containing all four elements:
An identifiable patient
An identifiable reporter
A suspect drug
An adverse event or fatal outcome 10

13. Forms 3500A (Medwatch Form)
Council for International Organization of Medical Science (CIOMS I Foreign) or other form if approved in advance 11

14. The Headquarter/Field Adverse Event Team
The headquarters scientists use adverse event reports to evaluate the safety of marketed drugs
OC/ADE Team coordinates between regulatory and scientific staff.
The field investigators assure industry compliance with reporting regulations 12

15. Role of the Field Investigator
To verify through on-site visits that firms are submitting all required reports of adverse events to FDA and the reports are complete, accurate and timely. 13

16. Role of the Field Investigator
When reports of adverse events are not
submitted, or are incomplete, inaccurate
or late, then document to support
appropriate regulatory action. 14

17. Role of the Field Investigator
Look for adverse events not cited on the product labeling.
Do not make medical evaluation of adverse events.
Do not evaluate labeling or make labeling change recommendations 15

18. Selection of the Firms Risk Management Approach
Firms with ADE reporting problems
Firms with prior violative history
Recalls
AIP list
NDA field alerts
High-risk drugs 16

19. References Used Prior, During and After Inspection
CP , Enforcement of the Postmarketing Adverse Drug Experience Reporting Regulations.
Regulations
Guidance documents
Inspectional package 17

20. SOPs
Procedure to specify the minimum qualifications of persons involved in investigating and evaluating ADEs
Make sure that current reporting requirements are cited in SOPs
SOPs should specify control activities to ensure that ADEs are investigated, followed-up, evaluated and sent to FDA. 18

21. Source Documents Complaint logs - numerical for completeness
Medical Department Logs
Distribution records
Annual product reviews 19

22. We are looking for...
Outcomes to identify problem areas for inspectional coverage.
What system failure(s) caused the firm not to comply with the regulations. 20

23. Look for Discrepancies such as...
Omissions
Minimizing results
Lack of follow-up
Inadequate follow-up 21

24. Significance of Deviations
Most serious - not submitting 15-day reports
Serious - report accuracy
Moderately serious - timeliness 22

25. If reports are found that have not been filed...
Determine the nature of the event and the cause for failure to report.
Determine what changes have been made to prevent reoccurrence. 23

26. When Discrepancies are Found
Review raw data
Ask questions and understand how the event and investigation was handled
Look for patterns or trends
Document 24

27. Type of Violations Uncovered
Serious and unlabeled events not submitted in a timely manner (range 30 days up to ten years
Lack of assurance that all ADEs were submitted
Foreign serious and unlabeled events not submitted from foreign affiliates 25

28. Cont. Violations Uncovered
Failure to conduct prompt and adequate follow-up investigations of ADEs
Serious and unlabeled events not assessed properly
No periodic reports submitted 26

29. Cont. Violations Uncovered
Computer system used to process and generate ADR reports is not validated
Coding errors in Medwatch forms
No approved SOPs 27

30. Remember
Scientific evaluation of adverse events depends upon the field investigator assuring that industry submits reports that are complete, accurate, and timely. 28

31. For Additional Information...Contact the Surveillance Program Team
Jay Schmid –
Carol Krueger –
Juliaette Johnson –
Denis Mackey – 29

32. Internet Sites for ADR Information 30